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Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes

Author

Lewis MJ1, Barnes MR2, Blighe K1, Goldmann K1, Rana S3, Hackney JA4, Ramamoorthi N5, John CR1, Watson DS6, Kummerfeld SK4, Hands R1, Riahi S1, Rocher-Ros V1, Rivellese F1, Humby F1, Kelly S1, Bombardieri M1, Ng N1, DiCicco M1, van der Heijde D7, Landewé R8, van der Helm-van Mil A7, Cauli A9, McInnes IB10, Buckley CD11, Choy E12, Taylor PC13, Townsend MJ14, Pitzalis C15. Cell Rep. 2019 Aug 27;28(9):2455-2470.e5. doi: 10.1016/j.celrep.2019.07.091.

Author Information

1 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

2 Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Alan Turing Institute, British Library, London NW1 2DB, UK.

3 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

4 Bioinformatics and Computational Biology, Genentech Research & Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.

5 Biomarker Discovery OMNI, Genentech Research & Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.

6 Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Alan Turing Institute, British Library, London NW1 2DB, UK; Oxford Internet Institute, University of Oxford, Oxford OX1 3JS, UK.

7 Department of Rheumatology, Leiden University Medical Center, the Netherlands.

8 Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, the Netherlands.

9 Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy.

10 Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.

11 Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

12 Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.

13 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

14 Biomarker Discovery OMNI, Genentech Research & Early Development, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: townsend.michael@gene.com.

15 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: c.pitzalis@qmul.ac.uk.

Abstract

There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.